Much like a weird physics experiment, our perception of pain intensity can be affected by our expectations. Information about expectations—the driver of the placebo effect—travels from the cortex to groups of cells in the brainstem, which then modulate pain signals in the spinal cord, according to a new study from a team of investigators at the University of Sydney. Findings from the new study were published recently in The Journal of Neuroscience through an article titled, “Brainstem mechanisms of pain modulation: a within-subjects 7T fMRI study of Placebo Analgesic and Nocebo Hyperalgesic Responses.”

The Australian researchers measured brainstem activity with high-resolution functional MRI (fMRI) in participants as they rated the pain of a hot stimulus applied to their arm. The team conditioned participants to think three types of cream had been applied to their arm: a pain-relieving cream with lidocaine, a heat-intensifying cream with capsaicin, and Vaseline. In reality, all three creams were Vaseline, and any perceived differences in pain came from the placebo or nocebo effect (imagined increases in pain).

A summary of brainstem regions in which signal intensity changes are significantly correlated to placebo or nocebo abilities reveals that the midbrain periaqueductal gray (PAG)—rostroventromedial medulla (RVM) pathway displays opposing responses. That is, signal changes in the PAG are negatively correlated with placebo-ability but positively correlated with nocebo-ability and vice versa for the RVM. Colored lines indicate major descending pathways within the brainstem: blue = PAG-RVM axis, green = reticular-spinal cord projections, red = spinal projections from the LC. [Crawford et al., JNeurosci 2021]
“This study employed ultra-high field 7 Tesla fMRI to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25; 12 Male),” the authors wrote. “Over two successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled ‘lidocaine’ (placebo) and ‘capsaicin’ (nocebo) were acting to modulate their pain relative to a third ‘Vaseline’ (control) cream.”

Furthermore, the authors noted that “in a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected, and placebo and nocebo responses were determined. Brainstem-specific fMRI analysis revealed altered activity in key pain-modulatory nuclei, including disparate recruitment of the periaqueductal gray (PAG)—rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in their engagement of the substantia nigra and locus coeruleus.”

Placebo and nocebo effects influenced activity in the same brainstem circuit but in opposite ways. The strength of the placebo effect was linked to increased activity in an area called the rostral ventromedial medulla and decreased activity in a nucleus called the periaqueductal gray; the nocebo effect induced the opposite change. These results reveal the role of the brainstem in pain modulation and may offer a route for future treatments of chronic pain.

“These data reveal that placebo and nocebo effects are generated through the differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influence the experience of pain by modulating activity at the level of the dorsal horn.”